Pharmacological receptors are intracellular or membrane-bound proteins which produce a pharmacological effect after binding with a specific ligand. In this regard, a pharmacological receptor has a dual function to (a) detect a ligand signal by forming a ligand-receptor complex and to (b) conduct and translate the signal leading to the pharmacological effect.
Drugs can replace endogenous physiological ligands to interact with receptors. A prerequisite for such a drug-receptor interaction is the formation of a drug-receptor complex, just as in the case of ligand-receptor interaction. In contrast to physiological ligands that stimulate an effect after binding to a receptor (receptor-mediated effects), drugs can be classified as (a) agonists or drugs which stimulate an effect after binding to the receptor, and (b) antagonists or drugs which do not stimulate an effect after receptor binding.
Several types of molecular interactions are possible for drug-receptor binding including ionic bonds, hydrogen bonds, and hydrophobic bonds by van der Waals forces. The vast majority of receptor interactions involve several kinds of binding simultaneously. Ionic bonds are important for the primary phase of drug-receptor interaction since these bonds have the greatest or longest range. After the initial interaction, fine-tuning takes place involving dipole-dipole-bonds, hydrogen bonds and hydrophobic bonds. Although all these interactions also fix the drug molecule in the receptor's active site, the bindings are nevertheless reversible, as the force of interaction is very weak. Hence the pharmacological effectiveness of any drug is often affected by its own concentration in the plasma, as a decrease in plasma drug concentration will increase the dissociation of drug molecule from its receptor.
Several agents are known to inhibit enzymes irreversibly or pseudoirreversibly and the precise mechanism of inhibition gives rise to subtle differences in the inhibition profiles and the duration of inhibition.
Many inhibitors of acetylcholinesterase react covalently with this enzyme to form an acyl enzyme that deacylates more slowly than the acetyl enzyme formed with the natural substrate acetylcholine. The acetyl enzyme forms rapidly by attack of the active site serine on the substrate. Transfer of the acyl group to the enzyme occurs through a tetrahedral intermediate. The acetyl enzyme is rapidly hydrolyzed, with a halftime of 10 μsec. These rapid acylation and deacylation steps give rise to a turnover rate of 105 substrate molecules per enzyme molecule per second. Cholinesterase inhibitors such as physostigmine and neostigmine form methylaminocarbamyol and dimethylaminocarbamoyl enzymes, which have half times for deacylation of several minutes. Thus, by providing the enzyme with an alternative substrate, catalysis of acetylcholine is precluded during the catalytic cycle for the carbamoylating agent. The kinetic constants for the respective acylation steps for the acetoxy and carbamoxy ester substrates do not greatly differ; hence the longer residence time of the carbamoyl enzyme conjugate is an important factor in favoring inhibition.
Several other enzymes are inhibited by covalent attachment of the inhibitor, giving rise to irreversibility. The hydrazines (phenelzine, isocarxazid metabolites) and the acetylenic agents (pargyline) are oxidized to reactive intermediates by monoamine oxidase. These intermediates attack the associated flavin cofactor on the enzyme. Such agents have been termed suicide substrates since their activation requires catalysis by the very enzyme that they inactivate. Hence the inactivation process is mechanism-based. There are now many examples of such substrates, activation of which by the enzyme results in covalent modification of the enzyme or of an associated cofactor. Often this occurs by conjugation or association of the enzyme with its substrate followed by a neighboring group attack. Several of the targets of suicide substrates have therapeutic significance. These include the penicillinases and alanine racemases in antibacterial design; GABA transaminase inhibitors for antiepileptic agents; lipoxygenase and cyclooxygenase inhibitors to control leukotriene and prostaglandin biosynthesis, respectively, aromatase inhibitors to block formation of estrogenic hormones; ornithine decarboxylase inhibitors as antiparasitic agents; and dopamine β-hydroxylase inhibitors to control catecholamine biosynthesis. Many suicide substrates serve as antimetabolites and are potential antineoplastic agents. The effectiveness of these inhibitors depends not only on their relative dissociation constants or Km values compared with those of the endogenous substrate but also on kinetic competition between turnover of the suicide substrate and the inactivation event.
Omeprazole (PRILOSEC) is another well-known irreversible binding drug that has been released for clinical use. This drug inhibits gastric acid secretion by binding to the H+, K+-ATPase present only in the apical membrane of parietal cells. Omeprazole is especially useful in patients with hypergastrinemia and may be valuable in those whose peptic ulcer disease is not well controlled by H2 antagonists. Omeprazole contains a sulfinyl group in a bridge between substituted benzimidazole and pyridine rings. At neutral pH, this drug is a chemically stable, lipid-soluble, weak base that is devoid of inhibitory activity. This neutral weak base reaches parietal cells from the blood and diffuses into the secretory canaliculi, where the drug becomes protonated and thereby trapped. Protonated drug rearranges to form a sulfenic acid and a sulfenamide. The sulfenamide interacts covalently with sulfhydryl group at critical sites in the extracellular (luminal) domain of the membrane-spanning H+, K+-ATPase. Omeprazole must thus be considered as prodrug that needs to be activated to be effective.
Despite the availability of several agents that bind their targets irreversibly, there is a dearth of methods currently available for rationally designing ligands to irreversibly bind a target receptor.